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CN102348691B - Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenyiethoxy) hexyl]amino}-l- hydroxyethyl)-8-hydroxyquinolin-2(1h)-one. - Google Patents

Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenyiethoxy) hexyl]amino}-l- hydroxyethyl)-8-hydroxyquinolin-2(1h)-one. Download PDF

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CN102348691B
CN102348691B CN201080011909.7A CN201080011909A CN102348691B CN 102348691 B CN102348691 B CN 102348691B CN 201080011909 A CN201080011909 A CN 201080011909A CN 102348691 B CN102348691 B CN 102348691B
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CN102348691A (en
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卢兰达·马尔舒埃塔·埃雷乌
恩里克·莫伊斯·瓦尔斯
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Abstract

A process for preparing the compound of formula (I), or a Pharmaceutically acceptable salt thereof, (I) which process comprises: reacting, in a xylene solvent, a compound of formula (V) with the compound of formula (IV) to give a compound of formula (III) followed by a P1 deprotection step and a P2 deprotection step.

Description

Manufacture the method for 5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one
[technical field]
The present invention relates to the modification method of a kind of manufacture 5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one and pharmaceutically acceptable salt thereof.
[background technology]
5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one (compound (I)) with and manufacture method be described in WO 2006122788 A1.
The napadisilate (napadisylate) of 5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one with and manufacture method be described in WO 2008095720 A1.
Inventor now finds unexpectedly, by the synthetic method described in change WO 2006122788 A1 and WO 2008095720 A1 can (a) increase compound (I) with and productive rate, (b) of salt make minimum and/or (c) Reaction time shorten of impurity level in final product.
These orders can be by selecting specific solvent and/or change or even removing some purification steps and realize, and Reaction time shorten thus increases the overall yield of final product simultaneously.In addition, method of the present invention is more suitable in extensive manufacture.
WO 2006122788 A1 describe the three-step approach of a kind of 5-of preparation (2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one,
WO 2008095720 A1 disclose the naphthalene disulfonic acid salt compound method of a kind of preparation formula (Ia):
Figure BPA00001434101500022
*e.e.: enantiomerism is excessive
Therefore, for according to disclosed technology in prior art, by intermediate (V) and (IV) the naphthalene disulfonic acid salt compound of preparation formula (Ia), must carry out four reactions steps, once wherein obtain after each intermediate, i.e. in addition separation and purifying, then as the initial substance in subsequent step.Use conventional purification process as known in the art (for example solvent extraction or chromatographic technique) to carry out purification step of the prior art.The overall yield of preparing naphthalene disulfonic acid salt compound (Ia) is approximately 9.5% as calculated, and the foreign matter content of simultaneously measuring by high performance liquid chromatography (HPLC) analysis is about 5-6%.
Find unexpectedly, (2-{[6-(2 for preparation 5-, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido-1-hydroxyethyl)-oxine-2 (1H)-one with and the method for salt can improve significantly by change reaction conditions (especially change or even remove the purge process in some steps), simplify thus many reactions steps, increase the overall yield of reaction simultaneously.In addition, had been found that with former method and compare, by suitable selective solvent, required product can higher yields and is obtained with purer form.
[summary of the invention]
Therefore, the invention provides 5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H) the-one compound of a kind of preparation formula (I) or the method for its pharmaceutically acceptable salt,
Figure BPA00001434101500031
Described method comprises:
A) in xylene solvent, make the compound of formula (V) and the 6-of formula (IV) (the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-1-amine reaction, thereby the compound of the formula of obtaining (III),
Figure BPA00001434101500041
P wherein 1and P 2represent that hydroxyl protecting group and L are leaving group,
Figure BPA00001434101500042
B) carry out P 1deprotection steps and P 2deprotection steps, to remove described protecting group P 1and P 2and obtain the compound of formula (I).
Conventionally,
(i) under the temperature range of 30 ℃-60 ℃, carry out P 2maximum 8 hours of deprotection steps, and/or
(ii) under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester, carry out P 1deprotection steps.
In xylene solvent, carry out step (a).In contrast to this, in WO 2006/122788, disclosed respective reaction step is carried out in methyl-sulphoxide (DMSO).Unexpected discovery of the present invention is to use especially xylene solvent can significantly improve the purity of the compound of formula (III).
In a preferred embodiment, above-mentioned steps (b) comprising:
-compound of formula (III) is carried out to described P 2deprotection steps, thereby the compound of the formula of obtaining (II),
Figure BPA00001434101500051
P wherein 1as hereinbefore defined; And
-compound of formula (II) is carried out to described P 1deprotection steps, thereby the compound of the formula of obtaining (I),
Therefore, in this embodiment, the invention provides 5-(2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one compound or its pharmaceutically acceptable salt method of a kind of preparation formula (I)
Figure BPA00001434101500061
Described method comprises:
A) in xylene solvent, make the compound of formula (V) and the 6-of formula (IV) (the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-1-amine reaction, thereby the compound of the formula of obtaining (III):
Figure BPA00001434101500062
P wherein 1and P 2represent that hydroxyl protecting group and L are leaving group,
Figure BPA00001434101500063
B) remove the protecting group of the compound of formula (III), thus the compound of the formula of obtaining (II),
Figure BPA00001434101500071
P wherein 1as hereinbefore defined; And
C) remove the protecting group of the compound of formula (II), thus the compound of the formula of obtaining (I):
Figure BPA00001434101500072
Conventionally, in this embodiment:
(i) under the temperature range of 30 ℃-60 ℃, carry out step b) maximum 8 hours, and/or
(ii) under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester, carry out step c).
In another embodiment, method of the present invention comprises:
A) in xylene solvent, make the compound of formula (V) and the 6-of formula (IV) (the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-1-amine reaction, thereby the compound of the formula of obtaining (III):
Figure BPA00001434101500073
P wherein 1and P 2represent that hydroxyl protecting group and L are leaving group,
Figure BPA00001434101500081
B) remove the protecting group of the compound of formula (III), thus the compound of the formula of obtaining (II '):
Figure BPA00001434101500082
P wherein 2as hereinbefore defined; And
C) remove the protecting group of the compound of formula (II '), thus the compound of the formula of obtaining (I):
Figure BPA00001434101500083
Conventionally, in this embodiment:
(i) under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester, carry out step b); And/or
(ii) under the temperature range of 30 ℃-60 ℃, carry out step c) maximum 8 hours.
P 1and P 2for hydroxyl protecting group.P 1and P 2can be identical or different.It is preferably difference.Skilled chemist can easily select to be suitable for P 1and P 2the hydroxyl protecting group of position.For example, T.W.Greene and G.M.Wuts, Protecting Groups in Organic Synthesis, the third edition, Wiley, New York, 1999 and the reference wherein quoted in suitable protecting group has been discussed.
Applicable hydroxyl protecting group example comprises: alkyl, such as methyl, ethyl and the tertiary butyl; Acyl group, alkyloyl for example, such as ethanoyl; Arylmethyl, such as phenmethyl (Bn), to mehtoxybenzyl (PMB), 9-Fluorene ylmethyl (Fm) and diphenyl methyl (diphenyl-methyl, DPM); Silylation, such as TMS (TMS) and tertiary butyl dimethylsilyl (TBS); With and similar group.
P 1be generally phenmethyl.In this embodiment, conventionally by means of hydrogenation, preferably such as palladium hydroxide (II) (Pd (OH) 2) or the catalyzer such as palladium (0) (Pd (0)) carry out P under existing 1deprotection steps.Catalyzer is preferably palladium (0)/charcoal.
Conventionally, under existing, the catalyzer that in this embodiment, in the amount with respect to reactant used, its amount is less than 10 % by weight, be preferably less than 5 % by weight, most preferably be approximately 4 % by weight carries out the hydrogenation of P1 deprotection steps.Use the catalyzer of this tittle conventionally can reduce produced foreign matter content.Particularly, it can reduce the formation of fluorine impurity, i.e. 5-(2-{[6-(2-phenyl ethoxy) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one.It also can reduce the formation of dihydroquinoline impurity.
P 2be generally tertiary butyl dimethylsilane base section.In this embodiment, conventionally by preferably such as tetrahydrofuran (THF) (tetrahydrofuran; THF) in equal solvent, fluoridize tetra-n-butyl ammonium (tetra-n-butyl ammonium fluoride, trihydrate with three hydrations; TBAF) reaction, or carry out P with hcl reaction in the solvent that is selected from ether, ester and alcohol 2deprotection steps.Preferably, in this embodiment, be selected from ether, t-butyl methyl ether (tert-butylmethylether; TBME), in the solvent of ethanol and isopropyl acetate, with hydrogenchloride, carry out P 2deprotection steps.
Or in this embodiment, preferably in tetrahydrofuran (THF) (THF) or 2-methyltetrahydrofuran, (preferably in THF) carries out P with TBAF 2deprotection steps.
Or, in this embodiment, preferably in tetrahydrofuran (THF) (THF), using naphthalene-1,5-disulfonic acid carries out P 2deprotection steps.
L is leaving group.Skilled chemist can easily select to be suitable for the leaving group of L position.The example of applicable leaving group comprises halogen atom, methylsulfonic acid ester group (O-S (O) 2-CH 3) and triflate (OS (O) 2-CF 3) base.
L is preferably halogen atom.L is bromine atoms more preferably.
Solvent used in step (a) does not basically contain DMSO conventionally.It does not more preferably basically contain DMSO and two
Figure BPA00001434101500101
alkane.
Compare with the similar approach that step (a) is carried out in such as DMSO equal solvent, the xylene solvent describing in detail more than using in step (a) can improve purity and/or productive rate generally.
In another embodiment of the present invention, under the temperature range of 40 ℃-50 ℃, carry out P 2deprotection steps is no more than 6 hours, is preferably no more than 4 hours, more preferably no more than 2 hours, for some time of maximum 1 hour most preferably.P 2the reaction times of deprotection steps shortens the formation that can reduce unexpectedly unfavorable by product.
In yet another embodiment, under existing, the tetrabutylammonium that is optionally about 0.3-0.9 gram TBAF/ gram reactant in amount carries out P 2the hydrogenation of deprotection steps.Described reactant is the compound of formula (II) normally.
In another embodiment of the present invention, by crystallization, come purifying by P 2the compound that deprotection steps obtains.Conventionally, use the alcoholic solution (preferred alcohol solution) of 1,5-naphthalene disulfonic acid to carry out crystallization.By crystallization but not come purifying by P by chromatography 2the compound that deprotection steps obtains can improve purity and/or productive rate.Preferably, in this embodiment, at P 1before deprotection steps, carry out P 2deprotection steps, therefore by P 2the compound that deprotection steps obtains is the compound of formula (II).
In a preferred embodiment of the invention, under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester, carry out P 1deprotection steps.Preferably, in this embodiment, described solvent is independent acetic acid or the mixture of acetic acid/methyl alcohol (1: 1), more preferably acetic acid/methyl alcohol (1: 1).
Conventionally, described solvent contain be less than 5% (v/v), be preferably less than 3%, be more preferably less than 1% any be not the liquid of acetic acid, alcohol and ester, being preferably any is not the liquid of acetic acid and methyl alcohol.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt of the compound of preparation formula (I).Described salt is preferably napadisilate or mesylate.
Napadisilate is the salt described in WO 2008/095720 normally.Napadisilate is preferably half napadisilate (heminapadisylate) or single napadisilate (mononapadisylate).Single napadisilate is conventionally containing naphthalene-1 of 0.8 to 1.2 molar equivalent of having an appointment, and 5-disulfonic acid/molar equivalent free alkali is more typically naphthalene-1 of approximately 1.0 molar equivalents, 5-disulfonic acid/molar equivalent free alkali.Half napadisilate is conventionally containing having an appointment 0.35 to 0.65 molar equivalent naphthalene-1, and 5-disulfonic acid/molar equivalent free alkali, is more typically approximately 0.5 molar equivalent naphthalene-1,5-disulfonic acid/molar equivalent free alkali.
The invention still further relates to the 5-that can obtain by method of the present invention (2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one or its pharmaceutically acceptable salt.Napadisilate or the mesylate of the 5-that preferably, the present invention relates to obtain by method of the present invention (2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one.Described salt is napadisilate more preferably.
Above mol ratio can be measured by standard technique, and described technology is for example 1h NMR, ultimate analysis and HPLC method.
When the napadisilate of the compound of preparation formula (I), conventionally after step (b), add naphthalene-1,5-disulfonic acid and 5-[2-{[6-(the fluoro-2-phenyl ethoxy of 2, the 2-bis-) hexyl of non-separate type (I)] amido }-1-hydroxyethyl)-oxine-2 (1H)-one.With which, carry out that final product is prepared in a cooking-pot type reaction (one-pot reaction) and not separated free alkali can improve purity and/or productive rate.In addition, because a described cooking-pot type reaction can realize larger process efficiency, so it is also favourable.
In a preferred embodiment of the invention, salify step is subsequently all in the situation that the intermediate reactions steps above not being obtained carries out purifying carries out step (b) and (while needing).
Can be by currently known methods or by carrying out the compound of acquisition formula (V) with the similar method of currently known methods.For example, can obtain P by the synthetic method described in US2004059116 (example 9C), WO2004/011416 (example 2) and WO2004/016578 (example 1ii) 1for phenmethyl and P 2compound for TBS.
By the synthetic method described in WO 2006122788 A1 (intermediate 9) obtain 6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-1-amine (IV).
Reagent and solvent used in the present invention are commercially available, for example, purchased from Aldrich Chemical Company company or Fluka Chemie GmbH.
Below the optimum condition for the process of step (a):
To 10.30-11.30 gram of (40-44 mmole) 6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-add 19.9 grams of (40 mmole) (R)-8-(benzyloxy)-5-(the bromo-1-of 2-(tertiary butyl dimethylsilyl oxygen base) ethyl) quinoline-2 (1H)-one (V) and 9-12 gram of sodium bicarbonate or 15-20 gram of salt of wormwood in the solution of 1-amine (IV) in 15-25 milliliter xylene solvent.Reaction mixture is heated to reflux in 4-6 hour.Be cooled to after room temperature inorganic salt that filtering-depositing goes out and washing with 80-120 milliliter dimethylbenzene.Remove solvent, obtain thus oiliness resistates, it can be used in next step without being further purified.
Below for P 2the optimum condition of deprotection steps:
The oiliness resistates being obtained by previous step is dissolved in 300-350 milliliter THF.Then 20-25 gram of TBAF is added in reaction medium.In 1-2 hour at 40 ℃-50 ℃ stirred reaction mixture.Be cooled to after room temperature, in vacuum, move down and desolventize.Water/the organic solvent of 250-300 milliliter (1: 1) is altogether added in resistates.Separated organic layer and by twice of organic solvent (2 * 20-30 milliliter) aqueous layer extracted.Merge organic layer and concentrate to remove solvent under vacuum.Preferred organic solvent for extraction treatment is toluene, methylene dichloride, isopropyl acetate or methyl-isobutyl--one (Methyl-Isobutyl-Ketone; MIK), more preferably toluene, isopropyl acetate or methylene dichloride, most preferably be isopropyl acetate or methylene dichloride.In alternative procedure, once remove after reaction solvent (THF), gained resistates can be processed the crystallization purifying be directly used in below on without aqueous extraction.
By using 8-9 gram of four hydration naphthalene-1, the 300-400 milliliter ethanolic soln crystallization of 5-disulfonic acid carrys out purifying resistates.Filter the product obtain and by 50-70 milliliter washing with alcohol.By ethanol/methylene (1: 2), methyl alcohol/isopropyl acetate (1: 2) or the methanol/toluene (1: 2) of 250-260 milliliter, process the wet cake obtaining.In this suspension, add the solution of 3.5-4 gram of NaOH in 170-190 ml water.In 40-50 minute at 20 ℃-30 ℃ stirred reaction mixture.Separated organic phase and move down and desolventize in vacuum.
Below for P 1the optimum condition of the process of deprotection steps
Intermediate (II) is dissolved in acetic acid/alcohol that cumulative volume is 160-170 milliliter (1: 1) (being preferably acetic acid/methyl alcohol).1-1.5 gram of 10%Pd/C, 50% water are added in solution.Then optionally an about 5-15 gram TBAF is added in solution.After several times purging with nitrogen gas, in 6-8 hour, at the temperature of 20 ℃-30 ℃, make reaction mixture hydrogenation being less than under 4 bar (preferably 1-2 bar).Follow filtering catalyst and wash by 190-200 ml methanol.About 200-250 milliliter acetic acid is added in filtrate and by 6-6.5 gram of four hydration naphthalene-1, and the solution of 5-disulfonic acid in the methyl alcohol/acetic acid (1: 1) of 50-70 milliliter is added in this filtrate.Mixture is heated to reflux and lasts 30 minutes.Be cooled to after room temperature filtration product and washing by 25-30 ml methanol.Optionally by the product that (such as under the boiling temperature of methyl alcohol) comes purifying to obtain with the formation of methanol slurries under hot state.Vacuum-drying final product (Ia) at 50 ℃.
Synthetic method described in the present invention will further illustrate by following instance.Only the mode with signal provides example and shall not be understood as limiting.
By 1h-NMR and mass spectroscopy (MS) confirm prepared compound structure.Use the Varian Gemini-200 NMR spectrograph operating under the frequency of 200 or 300 megahertzes to record NMR.Use tetramethyl silane as with reference to and by sample dissolution in deuterate methyl-sulphoxide (DMSO-d 6) or deuterate chloroform (CDCl 3) in.
By HPLC, be equipped with diode-array detector (diode array detector; DAD) and in the Alliance 2795 Waters instruments of ZMD or ZQ mass detector (electron spray ionisation) measure its purity.HPLC method is used Symmetry C18 tubing string (3.5 microns, 21 * 100 millimeters) and moving phase to form mutually by two: the buffering that A phase: pH is 3 (formic acid/ammonia) aqueous solution.B phase: 50.50 mixtures of the acetonitrile/methanol that contains ammonium formiate.Gradient is from 0% to 95% B phase in 10 minutes.
On the Gilson instrument being equipped with lower device, carry out preparation HPLC-MS test: binary pump (Gilson piston pump 321); Vacuum degasser (Gilson 864); Syringe-run tank (Gilson liquid treatment machine 215); Two injection module, i.e. analysis mode and preparative (Gilson 819); Valve (Gilson Valvemate 7000); 1/1000 splitter (Acurate of LC Packings); Make-up pump (Gilson 307); Diode-array detector (Gilson 170) and MS detector (Thermoquest Finnigan aQa has the quadrupole mass spectrometer that ES and APCI ionize pattern).HPLC-MS instrument is controlled by IBM PC.
experimental section
Comparative example I (according to WO 2006122788 and WO 2008095720):
Intermediate III.8-(benzyloxy)-5-((1R)-1-{[tertiary butyl (dimethyl) silylation] oxygen base }-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido } ethyl) quinoline-2 (1H)-one
To (4.80 grams of 8-(benzyloxy)-5-(the bromo-1-{[tertiary butyl of (1R)-2-(dimethyl) silylation] oxygen base } ethyl) quinoline-2 (1H)-one (V), 9.83 mmoles) and 6-(2, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] (3.04 grams of amine (IV), 11.8 mmoles) in the solution in methyl-sulphoxide (13.5 milliliters), add (2.49 grams of sodium bicarbonates, 29.4 mmoles) and sodium iodide (2.22 grams, 14.8 mmoles).At 140 ℃, heated mixt is 2 hours.After cooling, water (40 milliliters) diluting reaction thing and extracting with ether (2 * 20 milliliters).The organic extract that water (2 * 10 milliliters) and salt solution (20 milliliters) washing merge, dry (Na 2sO 4) and move down and desolventize in decompression.Acquisition is the title compound (6.40 grams, 98%) of oily matter.
Intermediate (II) .8-(benzyloxy)-5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl) quinoline-2 (1H)-one
In tetrahydrofuran (THF) (60 milliliters) solution of intermediate (III) (6.4 grams, 9.63 mmoles), add TBAF (5.02 grams, 19.26 mmoles).Under room temperature, stir the mixture and spend the night.In decompression, move down and desolventize.Pass through column chromatography, use methylene chloride/methanol (95: 5 to 85: 15) to carry out purifying as eluent, obtain being 8-(benzyloxy)-5-((1R)-2-{[6-(2 of oily matter, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido }-1-hydroxyethyl) quinoline-2 (1H)-one (II) (1.1 grams, 20%).
5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one (I)
In methyl alcohol (50 milliliters) solution of intermediate (II) (1.10 grams, 2.0 mmoles), add 20% palladium/charcoal (300 milligrams).Under 2 bar, make mixture hydrogenation 3 hours.Via diatomite filtration catalyzer and concentrated solvent.By silica gel column chromatography, with methylene chloride/methanol (95: 5) wash-out, carry out purifying gained oily matter, obtain being the title compound (0.50 gram, 54%) of oily matter.
5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one napadisilates (Ia)
By (6.63 grams of 5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one; 14.4 mmoles) be dissolved in 134 ml methanol, form 1.075M solution, be heated to approximately 50 ℃.Then by 7.74 mmole four hydration naphthalene-1,5-disulfonic acid is added in the solution of heating.Then under reflux temperature, stir the mixture 30 minutes and be then cooled to 20/25 ℃ and at this temperature, stir again 1 hour.By means of the formed throw out of filtering separation, with methanol wash and vacuum-drying at 50 ℃.(15.67 grams, 90%)
Example II (according to the present invention)
Intermediate III.8-(benzyloxy)-5-((1R)-1-{[tertiary butyl (dimethyl) silylation] oxygen base }-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido } ethyl) quinoline-2 (1H)-one
To [6-(2, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] (11.0 grams of amine (IV), 42.8 mmoles) in dimethylbenzene (20 milliliters) solution, add (19.9 grams of 8-(benzyloxy)-5-(the bromo-1-{[tertiary butyl of (1R)-2-(dimethyl) silylation] oxygen base } ethyl) quinoline-2 (1H)-one (V), 40.7 mmoles) and sodium bicarbonate (10.4 grams, 123 mmoles).Under refluxing, heated mixt is 6 hours.Be cooled to after room temperature, then wash by the inorganic salt that dimethylbenzene (176 milliliters) is added in reaction mixture and filtering-depositing goes out and with dimethylbenzene (100 milliliters).Under vacuum, the concentrated filtrate obtaining, to remove solvent, obtains oiliness resistates (intermediate (III)) thus, and it is not purified for next step.
Intermediate (II) .8-(benzyloxy)-5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl) quinoline-2 (1H)-one
Intermediate (III) is dissolved in tetrahydrofuran (THF) (330 milliliters).Then TBAF (23.3 grams, 73 mmoles) is added in this solution.In 1 hour, at 45 ℃, stir the mixture.Be cooled to after room temperature, in vacuum, move down water/methylene dichloride (1: 1) the mixture extraction gained resistates that desolventizes and optionally use 266 milliliters.Reclaim organic layer and then under vacuum, remove.Then add 352 milliliter of 96% ethanol and mixture is heated to 50 ℃-60 ℃.At this temperature, in 1 hour, add 8.5 gram of four hydration 1, the solution of 5-naphthalene disulfonic acid in 35 milliliter of 96% ethanol.By 29 milliliter of 96% washing with alcohol, add system, washings is added in reaction mixture.In 30 minutes under refluxing stirred reaction mixture and be then cooled to room temperature.Filtration product and by 60 milliliters of washing with alcohol.With 252 ml methanol/methylene dichloride (1: 2), process wet cake product.Then add the solution of 3.6 grams of NaOH in 116 ml waters and in 45 minutes at 20-25 ℃ stirred reaction mixture.Separated water layer and extracting with methylene dichloride (3 * 42 milliliters).Reclaim organic phase and stir together with the solution in 168 ml waters with 4.2 grams of NaCl.Separated organic phase and move down and desolventize in vacuum, obtain being thus 8-(benzyloxy)-5-((1R)-2-{[6-(2 of oily matter, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido }-1-hydroxyethyl) quinoline-2 (1H)-one (II) (16.8 grams, 75%).
5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one napadisilates (Ia)
In solution to intermediate (II) (16.8 grams, 30.5 mmoles) in methyl alcohol (69 milliliters) and in the mixture of acetic acid (77 milliliters), add 10% palladium/charcoal, the suspension of 50% water (1.33g) in the mixture of methyl alcohol (15 milliliters) and acetic acid (7 milliliters).Under 1-2 bar, make mixture hydrogenation 8 hours.Via diatomite filtration catalyzer and with methyl alcohol (193 milliliters), wash.Acetic acid (220 milliliters) is added in this filtrate.Then by four hydration naphthalene-1, the solution of 5-disulfonic acid (6.33 grams) in the mixture of methyl alcohol (54 milliliters) and acetic acid (27 milliliters) is slowly added in filtrate.In 30 minutes under refluxing reacting by heating mixture and be then cooled to room temperature.Filtering precipitate and washing with methyl alcohol (27 milliliters).The crude product that will wet is dissolved in methyl alcohol (800 milliliters) and was heated in 30 minutes and refluxes.Filtration product and use again methyl alcohol (34 milliliters) washing.The thus obtained solid of vacuum-drying at 50 ℃, obtain thus 5-((1R)-2-{[6-(2, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one napadisilates (14.9 grams, 81%).
5-((1R)-2-{[6-(2, the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido }-1-hydroxyethyl) overall yield of-oxine-2 (1H)-one napadisilates (Ia) is as calculated for approximately 60.7% (75% * 81%) and its purity are HPLC impurity=1.5%, e.e. > 98%.
Table 1: comparative result
*p 2deprotection steps
*p 1deprotection steps
Visible from table 1, in step (a), use xylene solvent significantly to reduce the impurity level in the intermediate of formula (III).In addition, compare with comparative example, the overall yield of 5-((1R)-2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-)-hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one napadisilate significantly increases, and impurity is reduced to lower aq.This result can be undertaken by changing some purification techniques, simplifies thus reactions steps, and reduces the amount of different reagent.

Claims (14)

1. the method for the 5-of a preparation formula (I) (2-{[6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-hydroxyethyl)-oxine-2 (1H)-one compound or its pharmaceutically acceptable salt,
Figure FDA0000424033720000011
Described method comprises:
A) in xylene solvent, make the compound of formula V and the 6-of formula (IV) (the fluoro-2-phenyl ethoxy of 2,2-bis-) oneself-1-amine reaction, thereby the compound of the formula of obtaining (III):
Figure FDA0000424033720000012
P wherein 1and P 2represent that hydroxyl protecting group and L are leaving group, described hydroxyl protecting group is independently: the alkyl that is selected from methyl, ethyl and the tertiary butyl, be selected from the alkyloyl of ethanoyl, be selected from phenmethyl, the arylmethyl to mehtoxybenzyl, 9-Fluorene ylmethyl and diphenyl methyl, be selected from the silylation of TMS and tertiary butyl dimethylsilyl; Described leaving group is to be selected from following group: halogen atom, methylsulfonic acid ester group and trifluoromethanesulfonic acid ester group,
Figure FDA0000424033720000013
B) carry out P 1deprotection steps and P 2deprotection steps, to remove described protecting group P 1and P 2and obtain the compound of formula (I);
Wherein:
(i) under the temperature range of 30 ℃-60 ℃, carry out described P 2maximum 8 hours of deprotection steps, and
(ii) under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester, carry out described P 1deprotection steps.
2. the method for claim 1, wherein step (b) comprising:
Compound to described formula (III) carries out described P 2deprotection steps, to obtain the compound of formula (II),
Figure FDA0000424033720000022
P wherein 1represent hydroxyl protecting group, described hydroxyl protecting group is: the alkyl that is selected from methyl, ethyl and the tertiary butyl, be selected from the alkyloyl of ethanoyl, be selected from phenmethyl, the arylmethyl to mehtoxybenzyl, 9-Fluorene ylmethyl and diphenyl methyl, be selected from the silylation of TMS and tertiary butyl dimethylsilyl; And
Compound to described formula (II) carries out described P 1deprotection steps, thereby the compound of the formula of obtaining (I),
Figure FDA0000424033720000023
3. the method for claim 1, wherein (a) P 1for phenmethyl and by hydrogenation, carry out described P 1deprotection steps, and (b) P 2for tertiary butyl dimethylsilyl and by fluoridizing tetra-n-butyl ammonium or carry out described P with hcl reaction with three hydrations 2deprotection steps.
4. the method for claim 1, wherein L is bromine.
5. the method for claim 1 is wherein used three hydrations to fluoridize tetra-n-butyl ammonium and is carried out described P in tetrahydrofuran (THF) 2deprotection steps.
6. the method for claim 1 is wherein carried out described P at the temperature of 40 ℃-50 ℃ 2deprotection steps is no more than for some time of 6 hours.
7. method as claimed in claim 6, wherein said for some time is no more than 4 hours.
8. the method for claim 1, it is for the preparation of half napadisilate or the mesylate of the compound of described formula (I).
9. method as claimed in claim 8, it is for the preparation of half napadisilate of the compound of described formula (I), wherein after step (b), add naphthalene-1,5-disulfonic acid and 5-[2-{[6-(the fluoro-2-phenyl ethoxy of 2, the 2-bis-) hexyl of not separated described formula (I)] amido }-1-hydroxyethyl)-oxine-2 (1H)-one.
10. method as claimed in claim 2, wherein passes through with four hydration naphthalene-1, and the ethanolic soln crystallization of 5-disulfonic acid comes purifying by described P 2the intermediate of the formula (II) that deprotection steps obtains.
11. the method for claim 1, wherein P 1for phenmethyl, and by the amount of the compound with respect to described formula (II), its amount is less than 10%(w/w) palladium/charcoal catalyst carry out hydrogenation under existing and carry out described P 1deprotection steps.
12. methods as claimed in claim 11, the consumption of wherein said catalyzer is less than 5%.
13. the method for claim 1, wherein when carry out described P under the mixture of acetic acid or acetic acid and alcohol or the existence of the admixture solvent of acetic acid and ester 1during deprotection steps, described solvent is methyl alcohol and the acetate mixture that acetic acid or ratio are 1:1.
14. methods as claimed in claim 13, wherein said solvent is that ratio is methyl alcohol and the acetate mixture of 1:1.
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